Katherine Conant, MD

Katherine Conant, MD

Professor
MD, Boston University School of Medicine
AB, Cornell University 
Research Building, Room EP-16
Phone: 202.687.8614
E-mail: kec84@georgetown.edu

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that can be released and/or activated in a neuronal activity dependent manner. MMP expression and activity can also be dramatically upregulated with injury, including that mediated by infection or hypoxia. Many studies have therefore focused on their role in brain pathology. Physiological release of MMPs is, however, critical to adaptive processes including learning and memory.

Our work is focused on the mechanisms by which MMPs influence neuronal and synaptic structure and function. We are particularly interested in their ability to cleave specific synaptic adhesion molecules and their ability to influence neuronal population activities important to mood and memory through modulation of the perineuronal net.

Perineuronal nets (PNNs) predominantly surround fast spiking GABAergic interneurons in brain regions including the cortex and hippocampus. Through varied mechanisms, including their ability to reduce membrane capacitance, these nets facilitate inhibitory neuronal transmission. PNNs may be pathologically increased or decreased in specific disease states including major depressive disorder. 

PNN and MMP mediated effects on neuronal structure and function are tested in varied models, including those related to disease. Present PhD students include Matthew Amontree, Katie Hummel, Katelyn Dial and Pauline Wonnenberg. Former PhD students include Doctors Megan Allen, Lorenzo Bozzelli, Seham Alaiyed, Griffin Greco, Ismary Blanco, and Karli Gilbert. 

Current Projects:

  1. PNN dysregulation in depression, and proteolysis as a mediator of antidepressant efficacy.  Studies are focused on the question of whether proteolysis can stimulate excitatory synapse formation and/or reduce inhibitory input to pyramidal cells.
  2. Dysregulated matrix deposition and/or proteolysis in AD and HIV related cognitive impairment.

Relevant Publications:

  1. Blanco, I., Caccavano, A., Wu, J. Y., Vicini, S., Glasgow, E., & Conant, K. (2024). Coupling of Sharp Wave Events between Zebrafish Hippocampal and Amygdala Homologues. The Journal of Neuroscience : the official journal of the Society for Neuroscience, e1467232024.
  2. Amontree, M., Nelson, M., Stefansson, L., Pak, D., Maguire-Zeiss, K., Turner, R. S., & Conant, K. (2024). Resveratrol differentially affects MMP-9 release from neurons and glia; implications for therapeutic efficacy. Journal of neurochemistry, 10.1111/jnc.16031.
  3. Amontree M, Deasy S, Turner RS, Conant K.Matrix disequilibrium in Alzheimer’s disease and conditions that increase Alzheimer’s disease risk. Front Neurosci. 2023 May 26;17:1188065. 
  4. Greco GA, Rock M, Amontree M, Lanfranco MF, Korthas H, Hong SH, Turner RS, Rebeck GW, Conant K. CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice. Neurobiol Dis. 2023 Apr;179:106057. 
  5. Alaiyed, S., McCann, M., Mahajan, G., Rajkowska, G., Stockmeier, C.A., Kellar, K.J., Wu, J.Y. & Conant, K. (2020) Venlafaxine stimulates an MMP-9-dependent increase in excitatory/inhibitory balance in a stress model of depression. Journal of Neuroscience40(22):4418-4431
  6. Bozzelli PL, Yin T, Avdoshina V, Mocchetti I, Conant KE, Maguire-Zeiss KA, HIV-1 Tat promotes astrocytic release of CCL2 through MMP/PAR-1 signaling. Glia. 2019 May 23. doi: 10.1002/glia.23642. PMID: 31124192
  7. Alaiyed S, Bozzelli PL, Caccavano A, Wu JY, and Conant K. Venlafaxine stimulates PNN proteolysis and MMP-9 dependent enhancement of gamma power; relevance to antidepressant efficacy. Journal of Neurochemistry 2019 148(6):810-821. PMI: 31058213
  8. Bozzelli PL, Alaiyed S, Kim E, Villapol S, and Conant K. Proteolytic Remodeling of Perineuronal Nets: Effects on Synaptic Plasticity and Neuronal Population DynamicsNeural Plasticity, Volume 2018, Article ID 5735789, 13 pages
  9. Jerome Sun, P. Lorenzo Bozzelli, Adam Caccavano, Megan Allen, Jason Balmuth, Stefano Vicini, Jian-Young Wu*, and Katherine Conant* Disruption of perineuronal nets increases the frequency of sharp wave ripple events, Hippocampus. 2018 Jan;28(1):42-52.
  10. Conant K, Daniele S, Bozzelli PL, Abdi T, Edwards A, Szklarczyk A, Olchefske I, Ottenheimer D, Maguire-Zeiss K.Matrix metalloproteinase activity stimulates N-cadherin shedding and the soluble N-cadherin ectodomain promotes classical microglial activation. J Neuroinflammation. 2017 Mar 17;14(1):56. doi: 10.1186/s12974-017-0827-4.
  11. Li Y, Chen X, Dzakpasu R, Conant K. Dopamine-dependent effects on basal and glutamate stimulated network dynamics in cultured hippocampal neurons. J Neurochem. 2017 Feb;140(4):550-560. doi: 10.1111/jnc.13915. Epub 2017 Jan 12.
  12. Allen M, Ghosh S, Ahern GP, Villapol S, Maguire-Zeiss, Conant KA. Protease induced plasticity: matrix metalloproteinase-1 promotes neurostructural changes through activation of protease activated receptor 1. Sci Rep. 2016 Oct 20;6:35497. doi: 10.1038/srep35497.
  13. Valente M, Allen M, Lim ST, *Conant K, *Grilli M. The MMP-1/PAR-1 axis enhances proliferation and neuronal differentiation of adult hippocampal neural progenitor cells, Neural Plasticity 2015;2015:646595 PMID:26783471
  14. Li Y, Partridge J, Berger C, Sepulveda-Rodriguez A, Vicini S, Conant K. Dopamine increases NMDA-stimulated calcium flux in striatopallidal neurons through a matrix metalloproteinase-dependent mechanism. Eur J Neurosci. 2016 Jan;43(2):194-203. PMID: 26660285
  15. Conant K, Allen M, Lim ST. Activity dependent CAM cleavage and neurotransmission. Frontiers in Molecular Neuroscience, 2015 Aug 11;9:305. PMID:26321910
  16. Lonskaya I, Partridge J, Lalchandani RR, Chung A, Lee T, Vicini S, Hoe H, Lim ST, Conant K. Soluble ICAM-5, a product of activity dependent proteolysis, increases mEPSC frequency and dendritic expression of GluA1. PLosOne 2013 Jul 2;8(7). e69136 doi: 10.1371/journal.pone.0069136. PMID:23844251 PMCID:PMC3699500
  17. Niedringhaus M, Chen X, Conant K, Dzakpasu R. Synaptic potentiation facilitates memory-like   attractor dynamics in cultured in vitro hippocampal networks. PLoS One.  2013;8(3):e57144. doi: 10.1371/journal.pone.0057144. Epub 2013 Mar 20. PMID: 23526935. PMCID:PMC3603961
  18. Niedringhaus M, Chen X, Dzakpasu R, Conant K. MMPs and soluble ICAM-5 increase neuronal excitability within in vitro networks of hippocampal neurons. PLoS One. 2012;7(8):e42631.
  19. Conant K, Lonskaya I, Szklarczyk A, Krall C, Steiner J, Maguire-Zeiss K, Lim ST. Methamphetamine-associated cleavage of the synaptic adhesion molecule intercellular adhesion molecule-5. J Neurochem. 2011 Aug;118(4):521-32. 
  20. Conant K, Wang Y, Szklarczyk A, Dudak A, Mattson MP, Lim ST. Matrix metalloproteinase-dependent shedding of intercellular adhesion molecule-5 occurs with long-term potentiation. Neuroscience 2010 Mar 17;166(2):508-21.
  21. Szklarczyk A, Beique J, Wang Y, Knorr D, Haughey N, Malpica T, Mattson M, Huganir R, and Conant K. MMP-7 cleaves the NR1 NMDA receptor subunit and modifies NMDA receptor function. FASEB J 2008 Nov;22(11):3757-67.
  22. Milward E, Kim K J, Szklarczyk A, Nguyen T, Melli G, Nayak M, Deshpande D, Fitzsimmons C, Hoke A, Kerr D, Griffin J W, Calabresi P A, and Conant K. Cleavage of Myelin Associated Glycoprotein by Matrix Metalloproteinases. Journal of Neuroimmunology 2008 Jan;193 (1-2):140-8.
  23. Milward, L, Fitzsimmons C, Szklarczyk A, and Conant K. The matrix metalloproteinases and CNS plasticity: An overview. Journal of Neuroimmunology. 2007 Jun 5 187(1-2):9-19
  24. Szklarczyk A, Stins M, Milward EA, Ryu H, Fitzsimmons C, Sullivan D, and Conant K. Glial activation and matrix metalloproteinase release in cerebral malaria. J Neurovirol.2007;13(1):2-118.
  25. Szklarczyk A., Oyler G., McKay R., Gerfen C., and Conant K. Cleavage of Neuronal SNAP-25 by Exogenous MMP-7. Journal of  Neurochemistry (2007) 102(4):1256-63
  26. Szklarczyk A, Conant K, Owens D, Ravin R, McKay R and Gerfen C. Matrix metalloproteinase-7 modulates synaptic vesicle recycling and induces atrophy of neuronal synapses.Neuroscience (2007) 149(1):87-98.
  27. Larson P, Giroux T, Conant K, and Yong VW. Myelin formation during development of the CNS is delayed in matrix metalloproteinase-9 and -12 null mice. Journal of Neuroscience2006 26:2207
  28. Conant K, St. Hillaire C, Nagase H, Visse R, Gary D, Haughey N, Anderson C, Turchan J, and Nath A. MMP-1 interacts with neuronal integrins and stimulates dephosphorylation of Akt.Journal of Biological Chemistry. 2004 Feb 27;279(9):8056-62.
  29. Conant K, St. Hillaire C, Anderson C, Galey D, Wang J, and Nath A. HIV-1 Tat and methamphetamine affect the release and activation of matrix degrading proteinases. Journal of  Neurovirology. 2004 Feb;10(1):21-8.
  30. Conant K, Haughey N, Nath A, St. Hillaire C, Gary DS, Pardo CA, Wahl LM, Bilak M, Milward E, and Mattson MP. Matrix metalloproteinase-1 activates a pertussis toxin-sensitive signaling pathway that stimulates the release of matrix metalloproteinase-9. Journal of  Neurochemistry. 2002 Aug;82(4):885-93
  31. Vawter, MP, Usen N, Thatcher L, Ladenheim B, Zhang P, VanderPutten DM, Conant K, Herman MM, van Kammen DP, Sedvall G, Garver DL, and Freed WJ. Characterization of human cleaved N-CAM and Association with Schizophrenia (2001) Experimental Neurology. 172:29-46.25.
  32. Vos C, Sjulson L, Nath A, McArthur JC, Pardo C, Rothstein J, Conant K.  Cytotoxicity by matrix metalloproteinase 1 in organotypic and dissociated neuronal cultures. Experimental Neurology 163:324-330, 2000.
  33. Vos C., Gartner S., Ransohoff R.M., McArthur J.C., Wahl L., Sjulson L., Hunter E., and Conant K. Matrix metalloprotease-9 release from monocytes increases as a function of differentiation: implications for neurodegeneration and neuroinflammation. Journal of Neuroimmunology. (2000) 109:221-227
  34. Conant, K., McArthur, J., Griffin, D., Sjulson, L., Wahl, L., and Irani, D. Cerebrospinal fluid levels of MMP-2, -7, and –9 are elevated in association with HIV dementia. Annals of  Neurology. (1999)  46:391-398.